NEUROCHEMICAL AND FUNCTIONAL CORRELATES OF NALTREXONE-INDUCED OPIATE RECEPTOR UP-REGULATION

  • 1 January 1985
    • journal article
    • research article
    • Vol. 232  (2) , 439-444
Abstract
The neurochemical and functional correlates of opioid receptor up-regulation after chronic antagonist administration in vivo and of down-regulation after withdrawal of antagonist were examined in rat brains. Total brain opioid receptors increased 1.9-fold by day 8 of naltrexone administration, after which no further increase was observed; the newly synthesized or unmasked receptors exhibited an enhanced sensitivity to guanyl nucleotide modulation. Withdrawl from chronic naltrexone treatment resulted in a return to nearly control levels of receptor density and guanyl nucleotide sensitivity in a period of 6 days. Up-regulation is apparently accompanied by an increased coupling of the receptors to the inhibitory guanyl nucleotide binding protein (Ni) and that down-regulation involves the dissociation of the receptor/Ni complex. In experiments designed to target opiate receptor subtypes, long-term treatment with naltrexone was found to produce a coordinated up-regulation of brain .mu. and .DELTA. receptors, but did not cause a significant change in the density or affinity of .KAPPA. or .SIGMA. receptors. These findings indicate that the .KAPPA. and .SIGMA. opiate receptor classes may be subject to independent control mechanisms. Chronic naltrexone treatment also resulted in an enhanced morphine-induced analgesia. A functional supersensitivity seemingly occurs in a result of the selective up-regulation of .mu. and .DELTA. receptors. After withdrawal from naltrexone, supersensitivity to morphine-induced analgesia decreased monotonically and in parallel to opioid receptor density, to prenaltrexone treatment levels within 6 days. A functional significance for antagonist-induced .mu. and .DELTA. opiate receptor up-regulation is suggested.